Enantioselective one-pot catalytic synthesis of 4,5-epoxy-3-alkanols and 1-Phenyl-2,3-epoxy-1-alkanols from α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/ejoc.201300397

Conformationally restricted perhydrobenzoxazines have been demonstrated to be good chiral ligands for one-pot asymmetric ethylation/epoxidation, and the unprecedented arylation/epoxidation of trisubstituted α,β-unsaturated aldehydes. The scope of the reaction has been studied and a wide set of substrates with allylic strain of different nature has been explored, obtaining good or total diastereoselectivities in all cases. The enantiocontrol was good or high for the ethylation/epoxidation reaction, whereas it remained at moderate or good levels for the arylation/epoxidation. The reaction is general for trisubstituted enals, and alkylic and aromatic substituents are tolerated at both the α- and β-position of the unsaturated aldehyde; however, disubstituted enals remain challenging substrates. When the one-pot and two-pot protocols were compared, no significant differences concerning the stereocontrol were found, so the advantages of the one-pot procedure are clear. Copyright

Full text of DOI:10.1002/ejoc.201300397

FULL PAPER
DOI: 10.1002/ejoc.201300397
Enantioselective One-Pot Catalytic Synthesis of 4,5-Epoxy-3-alkanols and
1-Phenyl-2,3-epoxy-1-alkanols from α,β-Unsaturated Aldehydes
Rebeca Infante,[a] Yulan Hernández,[a] Javier Nieto,*[a] and Celia Andrés*[a]
Keywords: Allylic compounds / Aldehydes / Asymmetric synthesis / Epoxides / Zinc
Conformationally restricted perhydrobenzoxazines have
been demonstrated to be good chiral ligands for one-pot
asymmetric ethylation/epoxidation, and the unprecedented
arylation/epoxidation of trisubstituted α,β-unsaturated alde-
hydes. The scope of the reaction has been studied and a wide
set of substrates with allylic strain of different nature has
been explored, obtaining good or total diastereoselectivities
in all cases. The enantiocontrol was good or high for the eth-
ylation/epoxidation reaction, whereas it remained at moder-
ate or good levels for the arylation/epoxidation. The reaction
is general for trisubstituted enals, and alkylic and aromatic
substituents are tolerated at both the α- and β-position of the
unsaturated aldehyde; however, disubstituted enals remain
challenging substrates. When the one-pot and two-pot proto-
cols were compared, no significant differences concerning
the stereocontrol were found, so the advantages of the one-
pot procedure are clear.
been devoted to the development of organocatalytic pro-
cesses that allow metal-free procedures.[7,8]
Introduction
One of the most important transformations in the field
of asymmetric synthesis is probably the enantioselective
epoxidation of alkenes. In 1965 a low level of stereoinduc-
tion was already obtained by Henbest, using (+)-peroxy-
camphoric acid.[1] However, 15 years later Sharpless and
Katsuki developed the first highly enantioselective epoxid-
ation of allylic alcohols. This well-known achievement al-
lowed high stereocontrol to be obtained in the epoxidation
of allylic alcohols, including the kinetic resolution (KR) of
secondary alcohols.[2,3] Such a discovery caused a revolu-
tion in enantioselective synthesis, because chiral epoxy
alcohols are one of the most useful building blocks for the
preparation of pharmaceutical and natural products.[2,4]
The original Sharpless–Katsuki asymmetric epoxidation re-
quires the use of catalytic amounts of titanium isopropox-
ide and tartrate ester ligands, tert-butyl hydroperoxide, and
molecular sieves. Nevertheless, many catalytic systems
based on transition metals have been developed since that
pioneering work, including titanium, vanadium, chromium,
manganese, iron, molybdenum or lanthanides, and allylic
and homoallylic alcohols or unfunctionalized olefins have
been used as substrates.[5,6] More recently, much effort has
Despite these excellent findings by Sharpless, nowadays,
KR is not the most convenient way to perform the synthesis
of chiral secondary epoxy alcohols because low conversions
are necessary to obtain good enantioselectivities. For this
reason, the synthesis of these compounds have been ac-
complished in two-step processes involving the isolation
and purification of the enantioenriched allylic alcohol, fol-
lowed by epoxidation employing different transition metals
and an oxidant, such as a peracid or a peroxide.[9] Experi-
mental studies have confirmed that the diastereoselectivity
of the process relies on both the allylic strain of the olefin
and on the nature of the oxidant agent.[10] Consequently,
obtaining similar levels of diastereocontrol in the epoxid-
ation of alcohols with different types of allylic strain (A1,2
or A1,3) with the same oxidant has usually been difficult. In
this context, to overcome this weakness, Walsh combined a
methodology based on asymmetric alkylation by means of
organometallic species to carbonyl compounds, followed by
Sharpless epoxidation. This protocol allowed the synthesis
of secondary epoxy alcohols with very good yields and
enantioselectivities.[11] Curiously, although a set of second-
ary and tertiary enantio- and diastereoenriched epoxy
alcohols were prepared by Walsh’s strategy, no examples of
directed arylation/epoxidation were included from alde-
hydes.
[a] Centro de Innovación en Química y Materiales Avanzados
(CINQUIMA) and Departamento de Química Orgánica,
Facultad de Ciencias, Universidad de Valladolid
Dr. Mergelina s/n, 47011 Valladolid, Spain
Fax: +34-983-423013
Based on the reported excellent results obtained in the
arylation, alkylation and alkynylation of aldehydes and α-
keto esters promoted by conformationally restricted chiral
perhydro-1,3-benzoxazines,[12] we decided to employ this
catalytic system as a chirality source to study the prepara-
tion of 1-phenyl-2,3-epoxy-1-alkanols employing Walsh’s
E-mail: javiernr@qo.uva.es
celian@qo.uva.es
Homepage: http://sintesisasimetrica.blogs.uva.es/
http://www.uva.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300397.
Eur. J. Org. Chem. 2013, 4863–4869
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4863

R. Infante, Y. Hernández, J. Nieto, C. Andrés
FULL PAPER
protocol. We were also interested in studying more exten- Table 1. One-pot asymmetric ethylation/epoxidation of α-methyl-
trans-cinnamaldehyde. Optimization of reaction conditions and
sively the scope and limitations of the ethylation/epoxid-
ation of a broad range of aldehydes using this method.
screening of perhydrobenzoxazine ligands 1–3.[a]
Results and Discussion
Enantioselective One-Pot Synthesis of 4,5-Epoxy-3-alkanols
Initially, the enantioselective formation of 4,5-epoxy-3-
alkanols from aldehydes in the presence of catalytic
amounts of perhydrobenzoxazines 1–3 (Figure 1) derived
from (–)-8-aminomenthol was explored. The first step of
this one-pot reaction involves the asymmetric addition of
dialkylzinc to the aldehyde, promoted by the chiral ligand,
whereas the second step concerns the epoxidation by an oxi-
dant[11,13] with or without titanium isopropoxide.
Entry
L
Solvent
T
[°C]
Time Yield[b] dr[c] ee[d]
[h]
[%]
6a/7a [%]
1
2
3
4
5
1
1
1
1
1
toluene
toluene
toluene
25
0
–20
–20
–20
4
88
92
96
92
94
87:13 90
89:11 94
12
24
24
24
97:3
97:3
95:5
95
93
94
hexane
toluene/hexane
(2:1)
6
7
2
3
toluene
toluene
–20
–20
24
24
86
90
93:7
97:3
92
71
[a] L/Et2Zn/aldehyde/tBuOOH/Ti(OiPr)4 = 0.04:2:1:1:0.1. [b] Yield
of isolated product. [c] Determined by 1H NMR analysis of the
crude reaction mixture. [d] Determined for the major diastereoiso-
mer by HPLC analysis employing a chiral column.
Figure 1. Perhydrobenzoxazines derived from (–)-8-aminomenthol.
Experiments were carried out at different temperatures
The enantioselective ethylation/epoxidation of α-methyl- for the oxidation step (Table 1, entries 1–3), and a maximal
trans-cinnamaldehyde was chosen as a model reaction to stereoselection was found in the reactions performed at
examine both the reaction conditions and the efficiency of –20 °C. When the reaction was run at 0 °C, the enantio-
these ligands.[14] For the ethylation step, the optimal condi- meric excess remained at the same level, but lower dia-
tions[12a] involved the use of two equivalents of diethylzinc stereoselectivity was observed (entry 2). In the same way, a
and catalytic amounts of ligand 1 (4 mol-%) at room tem- higher temperature produced a decrease of both enantio-
perature in toluene. We then focused on the reaction param- and diastereoselectivity (entry 1), although the reaction
eters that might affect the diastereo- and enantioselection time was significantly reduced. On the other hand, the sol-
of the epoxidation step, such as the oxidant, the tempera- vent employed (entries 3–5) did not affect the stereoselec-
ture, the solvent, and the presence or absence of titanium tion appreciably, and the best results were achieved in tolu-
isopropoxide.
ene (97:3 dr, 95%ee, entry 3). Concerning the structure of
Preliminary studies on the nature of the oxidizing agents the ligand, the effect of the substituent on the stereogenic
in the epoxidation step were carried out. In all cases, a solu- center that bears the hydroxyl group was also studied (en-
tion of α-methyl-cinnamaldehyde in toluene, 4 mol-% of li- tries 3, 6 and 7). The secondary alcohol 2 led to the product
gand 1, and 2 equiv. of diethylzinc were reacted at room with good enantioselectivity, albeit with slightly decreased
temperature, and the corresponding oxidant was then diastereoselection (entry 6). Conversely, replacement of the
added at –20 °C. After one hour, some reaction mixtures isopropyl group in 2 by an isopropenyl substituent (3, en-
were treated with titanium isopropoxide. In this way, the try 7) produced a significant drop in the enantiocontrol of
best result was obtained when tert-butyl hydroperoxide was the process.
used, and the erythro epoxy alcohol 6a could be synthesized
With the best reaction conditions established for α-
quantitatively and diastereoselectively using catalytic methyl-cinnamaldehyde, our interest turned to an explora-
amounts of titanium isopropoxide (dr 97:3). In the absence tion of the scope of the reaction and to an evaluation of
of titanium isopropoxide only a small amount of the epoxy the benefits of the one-pot protocol over the corresponding
alcohol was detected and a significant drop in the diastereo- two-step procedure. To this end, a series of diethylzinc ad-
selectivity was perceived (dr 67:33).
dition reactions to a set of unsaturated aldehydes with dif-
After determining a suitable combination of tert-butyl ferent substitution patterns were carried out by employing
hydroperoxide and titanium isopropoxide, the influence of the same chiral inductor; the results are collected in Table 2.
the solvent, the temperature of the oxidation step, and the It was observed that all substrates afforded the allylic
ligand was studied to achieve optimal diastereo- and alcohols in very good yields and good or perfect enantio-
enantioselectivities; the results are collected in Table 1.
selectivity (entries 1–13).
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Synthesis of Epoxy-Substituted Alkanols
Table 2. Catalytic asymmetric ethyl transfer to α,β-unsaturated aldehydes in the presence of 1.
Entry[a] Aldehyde
R1
R2
R3
Allylic alcohol
1 (4 mol-%)
1 (10 mol-%)
Yield [%][b]
ee [%][c]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4b
4c
4d
4e
4f
H
H
H
H
H
Me
Ph
Me
H
H
H
Ph
Ph
Et
Me
–(CH2)4–
Ph
Ph
Me
Me
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
95
90
89
89
87
97
96
84
93
97
96
94
86
90
98
87
97
93
95
91
–
96
97
–
93
99
97
98
87
94[d]
93
98
95
–
92
96[d,e]
88
H
H
H
H
H
H
H
Br
91
93
–
4g
4h
4i
5g
5h
5i
93
Ͼ99[d,e]
89
Ph
88[d]
83
86
91
81
4j
o-MeOC6H4
p-MeOC6H4
2-Furyl
Ph
5j
83
83
89
80
4k
4l
5k
5l
H
H
4m
5m
[a] 1/Et2Zn/aldehyde = 0.04/0.1:2:1. [b] Yield of isolated product after purification by flash chromatography. [c] Determined by HPLC
analysis employing chiral columns. [d] Absolute configuration was assigned by comparing the sign of specific rotation with literature
data. [e] To increase the sensitivity of the UV detection, these compounds were analyzed by chiral HPLC as the corresponding p-
nitrobenzoates.
The asymmetric ethylation/epoxidation of the above en-
als was studied, including several previously unexplored
acyclic and cyclic unsaturated aldehydes, with a range of
alkyl and aryl substituents at the α- and β-positions. The
results obtained for these known and unknown compounds
are summarized in Table 3. The one-pot ethylation/epoxid-
ation reactions occurred with good to excellent yields and
Figure 2. Proposed transition-state structure with the optimal dihe-
dral angles established by Adam and Wirth.
high diastereo- and enantiocontrol, independent of the sub-
stitution on the starting enal. Higher diastereoselectivities
were achieved for enals that lead to A1,3 strain instead of
A1,2 strain (see entries 6–8 vs. entries 1–5), and an inversion ingly, the very bulky bromine atom was not tolerated in the
in the diastereoselection of the process was observed. Thus, α-position (α-bromo-cinnamaldehyde, 4m) under the stan-
for enals leading to reaction intermediates with A1,2 strain, dard conditions, because no trace of the corresponding ep-
the major products were the corresponding erythro epoxy oxy alcohol were detected by 1H NMR spectroscopic analy-
alcohols (entries 1–5), whereas for enals leading to A1,3 sis, and the only isolated product was the corresponding
strain the principal products were the threo isomers (en- allylic alcohol (entry 13).
tries 6–8). Formation of the erythro or threo epoxy alcohol
Additionally, no effect in terms of diastereoselectivity
1
was determined by comparing the H NMR spectroscopic was perceived when the phenyl group at the β-position in
data of known products (entries 1, 5, and 8),[15] and was in 4a (Table 3, entry 1) was replaced by an alkyl substituent in
agreement with the transition-state structures proposed by 4c and 4d (entries 3 and 4). For example, the epoxy alcohol
Adam and Wirth, which establish a dihedral angle of be- 6d was isolated in high yield with 96:4 dr and 95%ee. Even
tween 70° and 90° for titanium complexes (Figure 2).[10] the erythro epoxy alcohol derived from cyclic aldehyde 4e
The configurations of the new compounds (entries 2–4, 6, was isolated in good yield with an excellent 96%ee (en-
and 7) were assigned by taking into account a well-known try 5). On the other hand, the process was diastereoselective
mechanism of diethylzinc addition[16] promoted by our li- and the enantioselectivity was high for enals leading to A1,3
gand[12a] and analyzing the allylic interactions in the transi- strain (90–94%ee), tolerating both alkyl and aryl substitu-
tion-states of the epoxidation step.
ents in R1 and R2 (entries 6–8).
The substitution of a methyl group for a larger group
In an attempt to further extend the scope of the reaction,
(such as phenyl) in R3 (A1,2 strain) did not influence signifi- we decided to explore the enantio- and diastereoselective
cantly the diastereo- or enantioselection (Table 3, entries 1 one-pot synthesis of disubstituted epoxy alcohols (Table 3,
and 2), and both epoxy alcohols 6a and 6b could be isolated entries 9–12). To this end, a range of trans-disubstituted
in high yields and with excellent stereoselection (97:3 dr, α,β-unsaturated aldehydes that lead to intermediates lack-
95%ee and 95:5 dr, 93%ee, respectively). However, surpris- ing allylic strains, were subjected to ethylation/epoxidation
Eur. J. Org. Chem. 2013, 4863–4869
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4865

R. Infante, Y. Hernández, J. Nieto, C. Andrés
FULL PAPER
Scheme 1. Synthesis of trisubstituted epoxy alcohols in two separate steps. Epoxidation of isolated enantioenriched allylic alcohols.
Table 3. One-pot catalytic asymmetric ethylation/epoxidation to ation/epoxidation protocol, and no signal of the desired ep-
1
several trisubstituted α,β-unsaturated aldehydes in the presence of
oxy alcohol could be identified in the H NMR analysis of
the crude reaction mixture.
1.
A comparison of the results summarized in Table 3 (eth-
ylation/epoxidation) and Table 2 (ethylation) indicates that
the optical purity of the allylic alcohols and their epoxy
analogues remained at similarly high levels, with only slight
differences in the ee values, mainly in favor of the epoxy
alcohols.
In addition, some of these enantioenriched unsaturated
alcohols were subjected to epoxidation to compare the dia-
stereo- and enantioselectivities with those obtained by the
one-pot approach (Scheme 1). The data revealed that nei-
ther the diastereo- nor the enantioselection was substan-
Entry[a]
4
R1
R2
R3 Yield[b]
[%]
dr 6/7[c]
(erythro/threo) [%]
ee[d]
tially modified, so the benefits of the one-pot protocol in
terms of operational simplicity are clear.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f Me
4g Ph
4h Me
4i
4j
4k
4l
H
H
H
H
H
Ph
Ph
Et
Me
–(CH2)4–
Ph
Ph
Me
Ph
Me
Ph
Ph
Ph
96
93
95
90
81
80
95
75
–
97:3
95:5
97:3
96:4
90:10
Ͻ1:99
Ͻ1:99
Ͻ1:99
–
95[e]
95
90
Enantioselective One-Pot Synthesis of 1-Phenyl-2,3-epoxy-
1-alkanols
95
96[e,f]
90
H
H
H
H
H
H
H
Br
Although some cyclic and acyclic epoxy alcohols were
prepared in a one-pot manner by Walsh et al. using (–)-
MIB as chirality source with excellent yields, diastereo- and
enantioselection, no precedents of the asymmetric synthesis
of 1-phenyl-2,3-epoxy-1-alkanols by one-pot phenylation/
epoxidation of unsaturated aldehydes have been reported.
Recently, we have reported excellent results for the enan-
tioselective arylation of an extensive set of aldehydes em-
ploying diethylzinc, 10 mol-% of ligand 1, and triarylborox-
ins as the aryl source. This process involves two steps: the
preparation of the arylating reagent in situ and the addition
to the carbonyl component.[12b] One important feature of
this arylation method is that both enantiomeric forms are
accessible with the same chiral ligand by means of the ap-
propriate combination of arylboronic acid or triarylboroxin
and aromatic aldehyde.
94
91[e,f]
–
9[g]
10
11
12
13
H
H
H
H
H
o-MeOC6H4
p-MeOC6H4
2-furyl
Ph
40
Ͻ10
–
52:48
n.d.
–
85 (84)
n.d.
–
4m
–
–
–
[a] 1/Et2Zn/aldehyde/tBuOOH/[Ti(OiPr)4]
=
0.04:2:1:1:0.1.
1
[b] Yield of isolated product. [c] Determined by H NMR analysis
of the crude reaction mixture. [d] Determined for the major dia-
stereoisomer by chiral HPLC analysis. The ee for the minor dia-
stereoisomer are given in parentheses. [e] Absolute configuration
was assigned by comparing the sign of specific rotation with litera-
ture data. [f] To increase the sensitivity in the UV detection, these
compounds were analyzed by chiral HPLC after transformation
into their corresponding benzoates. [g] The only product detected
was the corresponding allylic alcohol.
under optimal reaction conditions. Although no epoxid-
With these precedents in mind, we decided to extend this
ation of trans-cinnamaldehyde (4i) occurred (entry 9), fortu- study to the one-pot arylation/epoxidation of α,β-unsatu-
nately, the process took place when ortho- and para-meth- rated aldehydes to synthesize the challenging 1-phenyl-2,3-
oxy-cinnamaldehyde 4j and 4k were used as substrates (en- epoxy-1-alkanols. First, the preparation of the phenyleth-
tries 10 and 11). Whereas p-methoxy-cinnamaldehyde was ylzinc species in situ was performed in toluene by using tri-
epoxidized in very low yield (Ͻ 10%), the preparation of phenylboroxin and diethylzinc at 60 °C for 30 min.[12b]
the corresponding epoxy alcohol from the ortho counter- Next, addition of the chiral ligand and aldehyde was carried
part was possible in moderate yield with good enantiomeric out at 0 °C, and finally the epoxidation was run under the
excess for both diastereoisomers (6j and 7j), albeit with al- previously described standard conditions. This initial ex-
most complete absence of diastereoselection (entry 10). Un- periment demonstrated that no epoxidation occurred for α-
fortunately, a complex mixture was found when heteroaro- methyl-trans-cinnamaldehyde under such conditions, and
matic unsaturated aldehyde 4l was subjected to the ethyl- that the only isolated product was the allylic alcohol. How-
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Eur. J. Org. Chem. 2013, 4863–4869

Synthesis of Epoxy-Substituted Alkanols
ever, to our delight, an increase in the amount of the oxidiz- reasonable stereoselection, despite the absence of allylic
ing agent (to 3 equiv.) and titanium isopropoxide strain in the transition state (Table 4, entry 6). The configu-
(0.3 equiv.) led to formation of product 8a in good yield rations of alcohols 8d, 8i and 9i were assigned according to
(88%), with excellent diastereoselection (94:6 dr) and good reported data.[18] Analogously, the configurations of all new
enantioselectivity (87%ee). This result is noteworthy be- epoxy alcohols were assigned with regard to the allylic
cause removal of boron species from the reaction medium strain in the models proposed by Adam and Wirth,[10] and
before the epoxidation step is not necessary with this proto- taking into account the stereochemistry of the arylation
col.
To evaluate the scope of the one-pot phenylation/epoxid-
step for ligand 1.[12b]
In search of the origin of the moderate enantiocontrol,
ation reaction, additional acyclic α,β-unsaturated aldehydes the phenylation of the previous α,β-unsaturated aldehydes
were tested; the results are summarized in Table 4. All com- was carried out under the same conditions; the results ob-
pounds successfully underwent the phenylation/epoxidation tained are collected in Table 5. All products were isolated
process (entries 1–4 and 6), with the only exception being in good yields with moderate or good enantiocontrol. The
aldehyde 4g, which, in agreement with previous reports,[17] trisubstituted allylic alcohols 10a–d were isolated with
suffered decomposition during the epoxidation step and enantioselectivities ranging between 66 and 80%ee (en-
only a small amount of the epoxy alcohol could be isolated tries 1–4). In this case, allylic alcohol 10g derived from β-
(entry 5). The diastereocontrol was excellent for all trisub- phenylcinnamaldehyde was stable and could be analyzed by
stituted enals (entries 1–4), similar to the ethylation/epoxid- HPLC, although its enantiomeric excess reached just 52%
ation process, although the enantioselectivities were not as (entry 5). In addition, the disubstituted trans-cinnamal-
high as those obtained for the corresponding ethylated dehyde was phenylated in 94% yield and 82%ee (entry 6).
compounds.
In general, no significant differences in terms of ee were
found between the epoxides and the allylic alcohols, with
some exceptions in which the epoxy alcohols are afforded
with higher selectivities (see Table 4, entries 1 and 4, and
Table 5). The evolution of the conversion and enantio-
selectivity along reaction time for the epoxidation step of
4a showed a constant value for the enantioselectivity, show-
ing that the difference between the ee value of allyl alcohol
and the corresponding epoxy alcohol did not arise from
kinetic resolution during the epoxidation.
Table 4. One-pot catalytic asymmetric phenylation/epoxidation to
α,β-unsaturated aldehydes in the presence of
1
and tri-
phenylboroxin as aryl source.[a]
Table 5. Catalytic asymmetric phenyl transfer to α,β-unsaturated
aldehydes in the presence of 1 and triphenylboroxin as aryl
source.[a]
Entry
4
R1
R2
R3 Yield[b]
[%]
dr 8/9[c]
(erythro/threo)
ee[d]
[%]
1
2
3
4
5
6
4a
4b
4c
4d
4g Ph
4i
H
H
H
H
Ph Me
88
83
80
94:6
Ͼ99: 1
98:2
96:4
n.d.
87 (84)
79
Ph
Et
Ph
Ph
Entry
4
R1
R2
R3 Allylic alcohol Yield[b] ee[c]
79
[%]
[%]
Me Ph
74
73[e]
Ph
Ph
H
H
15[f]
77
n.d.
1
2
3
4
5
6
4a
4b
4c
4d
4g
4i
H
H
H
H
Ph
H
Ph
Ph
Et
Me
Ph
Ph
Me
Ph
Ph
Ph
H
10a
10b
10c
10d
10g
10i
93
95
91
87
90
94
73
80
82
66
52
82
H
71:29
80 (86)[e]
[a] 1e/(PhBO)3/Et2Zn/aldehyde/tBuOOH/[Ti(OiPr)4]
=
0.1:0.6:2.4:1:3:0.3. [b] Yield of product isolated after purification
by flash chromatography. [c] Determined by 1H NMR analysis
(n.d.: not determined). [d] Determined for major diastereoisomer
by HPLC analysis employing chiral columns. The ee for the minor
diastereoisomer is given in parentheses (n.d.: not determined).
[e] Configuration was assigned by comparing 1H NMR spectro-
scopic analysis and the sign of specific rotation with literature data.
[f] Decomposition of the product was observed.
H
[a] 1e/(PhBO)3/Et2Zn/aldehyde = 0.1:0.6:2.4:1. [b] Yield of product
isolated after purification by flash chromatography. [c] Determined
by HPLC analysis employing chiral columns (AS-H, OD, AD and
AD-H).
Surprisingly, in contrast to the ethylation/epoxidation
The greater simplicity of the one-pot protocol makes it
process, the phenylated/epoxidized products derived from the preferred procedure for the synthesis of this kind of
trans-cinnamaldehyde (8i and 9i) could be reached with compounds.
Eur. J. Org. Chem. 2013, 4863–4869
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4867

R. Infante, Y. Hernández, J. Nieto, C. Andrés
FULL PAPER
without further purification.[21] Ligands 1–3 were prepared accord-
Conclusions
ing to reported procedures.[12a,14]
A wide range of known and unknown 4,5-epoxy-3-alk-
anols could be prepared by one-pot ethylation/epoxidation
of cyclic and acyclic α,β-unsaturated aldehydes employing
perhydrobenzoxazine 1 as chiral inductor. An extensive
study was carried out to elucidate the scope and limitations
of this reaction. Several aldehydes possessing A1,2 and A1,3
strain showed complete tolerance for this methodology and
very high diastereo- and enantioselectivities were reached.
Disubstituted unsaturated aldehydes have been studied in
the one-pot ethylation/epoxidation and the reaction pro-
ceeded with good enantiocontrol, although with the ab-
sence of diastereoselection, for o-methoxycinnamaldehyde.
In addition, the unprecedented asymmetric one-pot phen-
ylation/epoxidation has been reported, involving the prepa-
ration of the arylating species in situ, further addition to
the unsaturated aldehyde, followed by epoxidation to yield
chiral 1-phenyl-2,3-epoxy-1-alkanols. With the objective of
comparing the results obtained for all epoxy alcohols with
respect to their corresponding allylic alcohols, an extensive
list of new enantioenriched compounds were isolated in
high or excellent yields and with moderate to total enantio-
selectivity by using ligand 1.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, copies of 1H and 13C NMR spectra, and
HPLC data are included.
Acknowledgments
The authors acknowledge financial support from the Spanish Min-
isterio de Ciencia e Innovación (MICINN) (project number
CTQ2011-28487/BQU) and the Junta de Castilla y León (GR168).
R. I. thanks the Junta de Castilla y León for a predoctoral fellow-
ship.
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Experimental Section
General Information: All reactions were carried out in anhydrous
solvents under an argon atmosphere in flame-dried glassware by
means of Schlenk techniques. 1H NMR (300 or 400 MHz) and
13C NMR (75 or 100 MHz) spectra were recorded in CDCl3.
Chemical shifts for protons are reported in ppm from tetramethyl-
silane, with the residual CHCl3 resonance as internal reference.
Chemical shifts for carbon atoms are reported in ppm from tet-
ramethylsilane and are referenced to the carbon resonance of the
solvent. Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m
= multiplet, br. = broad), coupling constants (Hz), and integration.
Specific rotations were measured using a 5-mL cell with a 1-dm
path length, and a sodium lamp, and concentration is given in g/
100 mL. Flash chromatography was carried out using silica gel
(230–240 mesh). Chemical yields refer to pure isolated substances.
TLC analysis was performed on glass-backed plates coated with
silica gel 60 and an F254 indicator, and visualized by either UV
irradiation or by staining with I2 or phosphomolybdic acid solu-
tion. Chiral HPLC analysis was performed using a Daicel Chiralcel
OD Column, Chiralpak AD-H or Chiralpak AS-H. UV detection
was monitored at 220 or 254 nm. HRMS were performed with a
quadrupole spectrometer and TOF analyzer.
Unless otherwise indicated, all compounds were purchased from
commercial sources and used as received. Aldehydes 4b[19] and 4f[20]
were synthesized from commercially available (2Z)-2,3-diphenyl-2-
propenoic acid and ethyl trans-β-methylcinnamate, respectively, by
reduction with LiAlH4 followed by Swern oxidation of the corre-
sponding alcohol. Racemic allylic alcohols were prepared by ad-
dition of Grignard reagents to the corresponding aldehydes. Race-
mic epoxy alcohols were synthesized from the corresponding race-
mic allylic alcohols by employing mCPBA and CH2Cl2 as solvent
at –20 °C. Triphenylboroxin was freshly prepared by heating phen-
ylboronic acid for 8 h at 110 °C in a conventional oven and used
4868
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Received: March 15, 2013
Published Online: June 25, 2013
Eur. J. Org. Chem. 2013, 4863–4869
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4869